Substituted phenyl and naphthyl esters of PGE{HD 2

ABSTRACT

Substituted phenyl and naphthyl esters of PGE2, 15-alkyl-PGE2, and 15(R)-15-alkyl-PGE2, and their racemic forms, and processes for producing them are disclosed. The products are useful for the same pharmacological and medical purposes as PGE2, 15-alkyl-PGE2, and 15(R)-15-alkyl-PGE2, and are also useful as a means for obtaining highly purified PGE2, 15-alkyl-PGE2, and 15(R)-alkylPGE2 products.

United States Patent [191 Morozowich [4 1 July/0,1975

[ SUBSTITUTED PHENYL AND NAPHTHYL ESTERS OF PGEZ [75] Inventor: Walter Morozowich, Kalamazoo,

Mich.

[73] Assignee: The Upjohn Company, Kalamazoo,

Mich.

[22] Filed: Nov. 23, 1973 21 App]. No; 418,387

[52] US. Cl. 260/395; 260/390; 260/468 D; 260/471 R; 260/473 R; 260/476 R; 260/999 [51] Int. Cl. C09B 11/06; C07C 69/074 [58] Field of Search 260/471 R, 390, 473 R, 260/479 R, 468 D, 395, 476 R [56] References Cited OTHER PUBLICATIONS Buehler, C. A, et al., Organic Synthesis, (1970), pub.

by Wileyl[nterscience of NY. (OD262B7) page 880 relied on.

Royals, E. E. Advanced Organic Chemistry, (1961), pub. by Prentice-Hall of NJ. (QD251R68C6) page 605 relied on.

Primary Examiner-Lorraine A. Weinberger Assistant ExaminerL. A. Thaxton Attorney, Agent, or Firml\ Iorris L. Nielsen 5 7] ABSTRACT 25 Claims, We Drawings 1 SUBSTETUTED PHENYL Alklll) l lrtill lll'lll lirlls ESTER; (11F 11 G112:

A systematic name for PGE is 7- {3o4-hydroxy-2/3- [(3S)-3-hydroxy-trans-1-octenyl]-5-oxo-1ocyclopentyl}-cis-5-heptenoic acid. F613 is known to be useful for a variety of pharmacological and medical purposes, for example labor induction and abortion in pregnant animals, including humans, menstrual regulation in both pregnant and non-pregnant animals, ineluding humans, reduction and control of gastric secretion, and as a hypotensive agent to reduce blood pressure in mammals, including humans. See Bergstrom, et al., Pharmacol. Rev. 20, 1 (1968) and references cited therein. As to racemic PGE- see for example W. P. Schneider, Chem. Commun. 304 (1969).

The l5-alkyl-PGE analog and its (R) epimer are represented by the formula:

6H3 0H, c H be, one OH, or CZHS as.

following the usual convention wherein broken line attachment of hydroxy to the side chain at carbon 15 indicates the natural or S configuration and solid line attachment of hydroxy indicates the epi or R configuration. See for example Nugteren, et al.. Nature 212, 38 (1966) and Cahn, J. Chem. Ed. 41, 116 (1964). The IS-alkyland 15(R)-15-alky1-PGE analogs in their optically active and racemic forms are known. See for example U.S. Pat. No. 3,728,382. These analogs are also useful for the above-described pharmacological purposes.

Esters of the above compounds are known, wherein the hydrogen atom of the carboxyl group is replaced by a hydrocarbyl or substituted hydrocarbyl group. Among these are the methyl ester of PGE (B. Samuelsson, J. Biol. Chem. 238, 3229 (1963)), the methyl ester of IS-methyI-PC-E (E. W. Yankee, et al., J. Am. Chem. Soc. 94, 3651 (1972)), the clecyl ester of PGlE (Belgian Pat. No. 765,732, Derwent Farmdoc No. 675805), the 2-phenoxyethyl ester of PGE (Belgian Pat. hlo. 776,294,1Derwent Farmdoc No. 3901 IT), the phenyl and alkyl-phenyl esters of PGE (British Pat. No. 1,282,661, see Derwent Farmdoc No. 6743811) and the p-(1,1,3,S-tetramethyl-butyl)-phenyl ester of PGE the or (and ,8- )naphthyl ester of PGE and the 5,6.'7,8-tetrahydro-2-naphthy1 ester of PGE (Belgian Pat. No. 775,106, Derwent Farmdoc No. 337051").

SUMMARY OF THE lNi/ENTION it is a purpose of this invention to provide novel ester derivatives of prostaglandin PGE IS-aIkyI-PGE l5(R)-15-a1kyl-PGE and their racemic forms. it is a further purpose to provide such esters derived from substituted phenols and naphthols. It is a further purpose to provide such esters in a free-flowing crystalline form. lt is still a further purpose to provide novel processes for preparing these esters.

The presently described esters include compounds represented by the generic formula:

wherein Z is the substituted phenyl or naphthyl group as defined immediately below, and Y is x ,M If M H CH, CH3 OH, Cpiig OH, CH (EH,

or CQHF, OH.

i.e., esters of PGE IS-methyI'PGE l5(R)-l5- methyl-PGE 15-ethyl-PGE and l5(R)-l5-ethyl- PGE and also the racemic compounds represented by each respective formula and the mirror image thereof; Z being represented by For example, PGE p-acetamidophenyl ester, is represented by formula III when Y is and Z is A, ie

and is conveniently identified herein as the PGE ester of formula llI-A. Racemic compounds are designated by the prefix racemic or dl; when that prefix is absent, the intent is to designate an optically active compound. Racemic lS-methyI-PGE pbenzamidophenyl ester, corresponds to formula III wherein Y is including of course not only the optically active isomer represented by formula Ill but also its mirror image.

The novel formula-III compounds and corresponding racemic compounds of this invention are each useful for the same purposes as described above for PGE and are used for those purposes in the same manner known in the art, including oral, sublingual, buccal, rectal, intravaginal, intrauterine, or topical administration.

For many applications these novel prostaglandin esters which I have obtained from certain specified phenols and napthols have advantages over the corresponding known prostaglandin compounds. Thus, these substituted phenyl and naphthyl esters are surprisingly stable compounds having outstanding shelf-life and thermal stability. In contrast to the acid form of these prostaglandins, these esters are not subject to acidcatalyzed decomposition either by elimination of water or by epimerization. Thus these compounds have improved stability either in solid, liquid, or solution form, In oral administration these esters have shown surprisingly greater efficacy than the corresponding free acids or lower alkyl esters, whether because of longer duration of biological activity or because of improved lipophilicity and absorption is not certain. These esters offer a further advantage in that they have low solubility in water and the body fluids and are therefore retained longer at the site of administration.

A particularly outstanding advantage of many of these substituted phenyl and naphthyl esters is that they are obtained in free-flowing crystalline form, generally of moderately high melting point, in the range 90l 80 C. This form is especially desirable for ease of handling, administering, and purifying. These crystals are highly stable, for example showing practically no decomposition at accelerated storage tests at 65 C., in comparison with liquid alkyl esters or the free acids. This quality is advantageous because the compound does not and Z is B, i.e.

lose its potency and does not become contaminated with decomposition products.

The crystalline esters also provide a means of purifying PGE l5-methyl-PGE l5(R)-l5-methyl-PGE l5-ethyl-PGE or l5(R)-l5-ethyl-PGE which are first converted to one of these esters, recrystallized until pure, and then recovered as the free acid. One method of recovering the free acid is by enzymatic hydrolysis of the ester, for example with a lipase. See German Pat. No. 2242792, Derwent Farmdoc No. 23047U.

To obtain the optimum combination of stability, duration of biological activity, lipophilicity, solubility, and crystallinity, certain compounds within the scope of formula lII are preferred.

One preference is that Z is limited to either O I C-NH--C*(Ca =-)a (3) -NH-E-R fl -MHE where'n R s Er- 0 M ii O-C- -NH-C-CH:.

Another preference is that Z is limited to O H c -NH-C-CHa N..'

H-'C|-CH:- I W-C-CH l I or Q/ i Another preference is that Z is further limited to wherein R. or

"yw'c' ca.

Especially preferred are those compounds which are in free-flowing crystalline form, for example:

p-acetamidophenyl ester of IGE p-benzamidophenyl ester of PGE p-(p-acetamidobenzamido)phenyl ester of PGE p-hydroxyphenylurea ester of POE:

p-biphenyl ester of PGE p-hydroxybenzaldehyde PGE p-acetamidophenyl ester of IS-methyl-PGE p-benzamidophenyl ester of IS-methyl-PGE- p-benzamidophenyl ester of l5(R)-15-methyl-1PGE or p-hydroxybenzaldehyde The substituted phenyl and naphthyl esters of PGE lS-aIkyI-PGE and l5(R)- l 5-alkyl-PGE encompassed by formula III wherein Z is defined by ester groups A. through T are produced by the reactions and procedures described and exemplified hereinafter. For convenience, the above prostaglandin or prostaglandin analog is referred to as the PG compound. The term phenol is used in a generic sense, including both phenols and napthols.

Various methods are available for preparing these esters, differing as to yield and purity of product. Thus, by one method, the PG compound is converted to a tertiary amine salt, reacted with pivaloyl halide to give the mixed acid anhydride and then reacted with the phenol. Alternately, instead of pivaloyl halide, an alkyl or phenylsulfonyl halide is used, such as p-toluenesulfonyl chloride. See for example Belgian Pat. Nos. 775,106 and 776,294, Derwent Farmdoc Nos. 33705T and 3901 lT.

Still another method is by the use of the coupling reagent, clicyclohexylcarbodiimide. See Fieser, et al., Reagents for Organic Synthesis, pp. 23 l236, John Wiley and Sons, Inc., New York (1967). The PG compound is contacted with one to ten molar equivalents of the phenol in the presence of 2-10 molar equivalents of dicyclohexylcarbodiimide in pyridine as a solvent.

The preferred novel process for the preparation of these esters, however, comprises the steps (1) forming a mixed anhydride with the PG compound and isobu- 'tylchloroformate in the presence of a tertiary amine and (2) reacting the anhydride with an appropriate phenol or naphthol.

The mixed anhydride is represented by the formula:

semicarbazone ester of semicarbazone ester of Lil lit) for the optically active PG compounds, Y having the same definition as above.

The anhydride is formed readily at temperature in the range 40 to (3., preferably at -10 to +1 0 C. so that the rate is reasonably fast and yet side reactions are minimized. The isobutylchloroformate reagent is preferably used in excess, for example 1.2 molar equivalents up to 4.0 per mole of the PG compound. The reaction is preferably done in a solvent and for this purpose acetone is preferred, although other relatively non-polar solvents are used such as acetonitrile, dichloromcthane, and chloroform. The reaction is run in the presence of a tertiary amine, for example triethylaminc, and the co-formed amine hydrochloride usually crystallizes out, but need not be removed for the next step.

The anhydride is usually not isolated but is reacted directly in solution with the phenol, preferably in the presence of a tertiary amine such as pyridine.

The phenol is preferably used in equivalent amounts or in excess to insure that all of the mixed anhydride is converted to ester. Excess phenol is separated from the product by methods described herein or known in the art, for example by crystallization. The tertiary amine is not only a basic catalyst for the esterification but also a convenient solvent. Other examples of tertiary amines useful for this purpose include N- methylmorpholine, triethylamine, diisopropylethylamine, and dimethylaniline. 2-methylpyridine and quinoline result in a slow reaction. A highly hindered amine such as 2,6-dimethyllutidine is not useful because of the slowness of the reaction.

The reaction with the anhydride proceeds smoothly at room temperature (about 20 to 30 C.) and can be followed in the conventional manner with thin layer chromatography (TLC), usually being found complete within l4 hours.

The reaction mixture is worked up to yield the ester following methods known in the art, and the products is purified, for example by silica gel chromatography.

Solid esters are converted to a free-flowing crystalline form on crystallization from a variety of solvents, including ethyl acetate, tetrahydrofuran, methanol, and acetone, by cooling or evaporating a saturated solution of the ester in the solvent or by adding a miscible nonsolvent such as diethyl ether, hexane, or water. The crystals are then collected by conventional techniques, c.g., filtration or centrifugation, washed with a samll amount of solvent, and dried under reduced pressure. They may also be dried in a current of warm nitrogen or argon, or by warming to about C. Although the crystals are normally pure enough for many applications, they may be recrystallized by the same general techniques to achieve improved purity after each recrystallization.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The invention can be more fully understood by the 60 following examples.

All temperatures are in degrees centigrade.

Silica gel chromatography, as used herein, is understood to include chromatography on a column packed with silica gel, elution, collection of fractions, and combination of those fractions shown by thin layer chromatography (TLC) to contain the desired product free of starting material and impurities.

TLC, herein, refers to thin layer chromatography.

PREPARATION 1 p-Benzamidophenol A solution of p-hydroxyaniline (20 g.) in 200 ml. of pyridine is treated with benzoic anhydride (20 g.). After 4 hr. at about 25 C., the mixture is concentrated under reduced pressure and the residue is taken up in 200 ml. of hot methanol and reprecipitated with 300 ml. of water. The product is recrystallized from hot acetonitrile as white crystals, 8.5 g., m.p. 218.0-218.5 C.

PREPARATION 2 p-(p-Acetamidobenzamido )phenol A solution of p-acetamidobenzoic acid (12.5 g.) in 250 ml. of tetrahydrofuran is treated with triethylamine (11.1 ml.). The mixture is then treated with isobutylchloroformate (10.4 ml.) and, after 5 min. at about 25 C., with p-aminophenol (13.3 g.) in 80 ml. of dry pyridine. After 40 min. the crude product is obtained by addition of 2 liters of water. The product is recrystallized from 500 ml. of hot methanol by dilution with 300 ml. of water as white crystals, 5.9 g., m.p. 275.0-277.0 C.

EXAMPLE 1 PGE p-Acetamidophe nyl Ester (Formula lIl-A).

A solution of PGE (0.215 v g.) and triethylamine (0.165 ml.) in 20 m1. of acetone is treated at C. with isobutylchloroformate (0.159 ml.) whereupon triethylamine hydrochloride is precipitated. After'5 min.

the mixture is treated with p-acetamidophenol (0.659

g.) in 5 ml. of pyridine for 3 hr. at about 25 C. The 501- vent is removed under reduced pressure and the residue taken up in acetonitrile and again concentrated.

The crude residue is dissolved in ethyl acetate and washed with aqueous citric acid (2%) and water. The organic phase is dried over sodium sulfate, concentrated, and triturated in hexane to apasty solid. The

EXAMPLE 2 PGE p-Benzamidophenyl Ester (Formula Ill-B).

A solution of PGE (0.26 g.) and triethylamine (0.206 ml.) in ml. of acetone is treated at 5 C. with isobutyl chloroformate (0.194 ml.), whereupon triethylamine hydrochloride is precipitated. The mixture is then treated with p-benzamidophenol (Preparation 1, 0.8 g.) in 8 m1. of pyridine for 4 hr. at about C. The solvent is removed under reduced pressure and the crude residue is subjected to silica gel chromatography, eluting with ethyl acetate followed by acetonitrile. The residue obtained by concentration of selected fractions is recrystallized from tetrahydroofuran-hexane (1:1) to yield the title compound, white free-flowing crystals, 0.269 g., m.p. l32.8135.0 C., having Rf 0.5 (TLC on silica gel in ethyl acetate); recrystallized from tetrahydrofuran-diethyl ether, m.p. l38.3139.5 C.

EXAMPLE 3 PGE p-(p-Acetamidobenzamido)phenyl Ester (Formula Ill-C) A solution of PGE (0.25 g.) and triethylamine (0.186 ml.) in 15 m1. of acetone is treated at 10 C. with isobutylchloroformate (0.202 ml.) and, after 5 min. at 0 to 5 C., with a solution of p-[(p'- acetamidophenyl)-carbamoyl]-phenol (Preparation 2, 0.96 g.) in 10 ml. of pyridine for 4 hr. at about 25 C. The solvent is removed under reduced pressure and the residue is partitioned between m1. of ethyl acetate and 100 ml. of 0.1 N. aqueous monosodium dihydrogen orthophosphate. The organic phase is dried over sodium sulfate and concentrated. The residue is taken up in 25 ml. of ethyl acetate, filtered, and the solution concentrated. The crude residue is dissolved in 1 ml. of dimethylformamide and 4 ml. of ethyl acetate and the solution subjected to silica gel chromatography, eluting with 3-8% methanol in ethyl acetate. The residue obtained by concentration of selected fractions is recrystallized from methanol-acetone (1:5) on addition of water, to yield the title compound, white free-flowing crystals, estimated 0.09 g., m.p. l73.2176.2 C., having Rf 0.5 (TLC on silica gel in ethyl acetate-methanol 92:8).

. EXAMPLE 4 p-Hydroxyphenylurea Ester of PGE (Formula Ill-E) Following the procedure of Example 1 but using 0.453 g. of PGE 0.27 ml. of triethylamine, 0.254 ml. of isobutylchloroformate, and 1.0 g. of phydroxyphenylurea, there is obtained a brown oily crude residue. This residue is dissolved in 100 ml. of ethyl acetate and 10 ml. of methanol, extracted with 0.1 N. aqueous hydrochloric acid and water, and the organic phase dried over sodium sulfate. The residue left on concentrating is subjected to silica gel chromatography, eluting with ethyl acetate-acetone (7:3) and ethyl acetate-acetone (2:3). The residue,obtained by concentration of selected fractions, 0.56 g., is recrystallized from 10 ml. of ethyl acetate on addition of one ml. of hexane as the title compound, white free-flowing crystals, 0.396 g., m.p. l05.3108.3 C., having Rf 0.5 (TLC on silica gel in ethyl acetate-acetone, 1:1).

EXAMPLE 5 PGE p-Biphenyl Ester (Formula lll-F) Following the procedure of Example 1 but using 0.51 g. of PGE 0.24 ml. of triethylamine, 0.226 ml. of isobutylchloroformate, and 0.49 g. of p-phenylphenol, there is obtained a crude oily residue which is taken up in ethyl acetate and concentrated several times. The brown oil is then subjected to silica gel chromatography, eluting with ethyl acetate containing 2% water. The residue obtained by concentration of selected fracltions, 0.735 g., is recrystallized from 6 ml. of ethyl acetate on addition of 12 ml. of hexane as the title compound, white free-flowing crystals, 0.585 g., mp. 91.892.8 C., having Rf 0.6 (TLC on silica gel in ethyl acetate).

EXAMPLE 6 PGE p-Tritylphenyl Ester (Formula III-G) Following the procedure of Example 1 but using 0.531 g. of PGE 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.760 g. of ptritylphenol, there is obtained a crude residue. The residue is subjected to silica gel chromatography, eluting with ethyl acetate. The residue obtained by concentration of selected fractions is recrystallized from ethyl acetate-hexane as the title compound, white freeflowing crystals, 0.165 g.) m.p. 96.397.8 C., having Rf 0.7 (TLC on silica gel in ethyl acetate).

EXAMPLE 7 N-Acetyl-L-tyrosinamide Ester of PGE (Formula Ill-H) Following the procedure of Example 1 but using 0.531 g. of PGE 0.254 ml. of triethylamine, 0.238 ml. of isobutylchloroformate, and 0.480 g. of N-acetyl-L- tyrosinamide, there is obtained a crude residue. The residue is subjected to silica gel chromatography, eluting with methanol-ethyl acetate mixtures. The residue obtained by concentration of selected fractions is dissolved in 10 ml. of warm acetone and diluted with ml. of hexane resulting in crystallization of the title com pound, as white, free-flowing crystals, 0.205 g., m.p. l37.3140.8 C., having Rf 0.2 (TLC on silica gel in ethyl acetate containing methanol).

EXAMPLE 8 N-Benzoyl-L-tyrosinamide Ester of PGE (Formula lIl-l) Following the procedure of Example 1 but using 0.531 g. of PGE 0.254 ml. of triethylamine, 0.238 ml. ofisobutylchloroformate, and 0.642 g. of N-benzoyl-L- tyrosinamide, there is obtained a crude residue. The residue is subjected to silica gel chromatography, eluting with ethyl acetate containing 10% methanol. The residue obtained by concentration of selected fractions is crystallized from acetone to yield the title compound, white free-flowing crystals, 0.240 g., m.p. 160.8164.8 C., having Rf 0.6 (TLC on silica gel in ethyl acetate containing 10% methanol).

EXAMPLE 9 p-Hydroxybenzaldehyde Semicarbazone Ester of PGE (Formula Ill-J) Following the procedure of Example 1 but using 0.516 g. of PGE 0.264 ml. of triethylamine, 0.249 ml. of isobutylchloroformate. and 1.4 g. of phydroxybenzaldehyde semicarbazone, there is obtained a crude oily residue. This residue is dissolved in ml. of acetonitrile and left at about 25 C. until the excess starting phenol crystallizes out and is then filtered off. The filtrate is concentrated and subjected to silica gel chromatography, eluting with acetonitrile followed by tetrahydrofuran-acetonitrile (3:2). The residue obtained by concentration of selected fractions, a white solid, 0.495 g.. is recrystallized, first from ethyl acetatehexane, then from hot acetonitrile, as the title compound, white free-flowing crystals, 0.328 g., m.p.

114 l25.3126.5 C., having Rf 0.4 (TLC on silica gel in tetrahydrofuranethyl acetate 3:2).

EXAMPLE l0 p-l-lydroxyacetophenone Ester of PGE (Formula lll-K) Following the procedure of Example 1 but using 0.561 g. of PGE 0.264 ml. of triethylamine, 0.249 ml. of isobutylchloroformate, and 0.312 g. of phydroxyacetophenone, there is obtained a crude oily residue. This residue is subjected to silica gel chromatography, eluting with water-ethyl acetate (1:99). The residue obtained by concentration of selected fractions, an oil, is triturated in hexane to yield a solid which is recrystallized from ethyl acetate-hexane to yield the title compound, white free-flowing crystals, 0.513 g., m.p. 76.8-77.8 C., having Rf 0.5 (TLC on silica gel in ethyl acetate).

EXAMPLE 1 l p-l-lydroxybenzamide Ester of PGE (Formula Ill-L) Following the procedure of Example 1 but using 0.561 g. of PGE 0.264 ml. of triethylamine, 0.243 ml. of isobutylchloroformate, and 0.5 g. of phydroxybenzamide, there is obtained a crude residue. This residue is subjected to silica gel chromatography, eluting with ethyl acetate-methanol (9:1). The residue obtained by concentration of selected fractions, an oil, 0.425 g., is crystallized from ethyl acetate-hexane to yield the title compound, white crystals, 0.294 g., m.p. 106.3108.3 C., having Rf 0.6 (TLC on silica gel in ethyl acetate-methanol (9:1

EXAMPLE l2 l5-Methyl-PGE p-Acetamidophenyl Ester (Formula Ill-A) Following the procedure of Example 1 but using 0.163 g. of IS-methyI-PGE 0.186 ml. of triethylamine, 0.174 ml. of isobutylchloroformate, and 0.538 g. of p-acetamidophenol, there is obtained a crude residue. This residue is dissolved in chloroform and left at about 25 C. until the excess starting phenol crystallizes out and is then filtered off. The filtrate is concentrated and subjected to silica gel chromatography, eluting with chloroform-acetonitrile (1:1) followed by acetonitrile. The residue obtained by concentration of selected fractions, an oil, 0.067 g., is crystallized from ethyl acetate on addition of hexane as the title compound, white free-flowing crystals, 0.042 g., m.p. l l4.3116.0 C., having Rf 0.6 (TLC on silica gel in ethyl acetate).

EXAMPLE 13 l5-Methyl-PGE p-Benzamidopheny Ester (Formula Ill-B) Following the procedure of Example 1 but using 0.176 g. of 15-methyl-PGE 0.133 ml. of triethylamine, 0.126 ml. ofisobutylchloroformate, and 0.900 g. of

' p-benzamidophenol, there is obtained a crude semisolid residue. This residue is partitioned between 100 ml. of chloroform and ml. of 0.1 N. aqueous monosodium dihydrogen orthophosphate. The organic phase is dried over sodium sulfate and concentrated to a white solid. The residue is subjected to silica gel chromatography, eluting with chloroform-ethylacetate (1:1) followed by acetone-ethyl acetate (1:4). The residue obtained by concentration of selected fractions, a v

colorless oil, 0.143 g., is crystallized from ethyl acetate on addition of hexane as the title compound, white free-flowing crystals, 0.126 g., m.p. ll9.8-l2l.8 C.,

having Rf 0.7 (TLC on silica gel in ethyl acetate).

EXAMPLE 14 15(R)-15 -Methy1-PGE p-Acetamidophenyl Ester (Formula lll-A) Following the procedure of Example 1 but using 0.200 g. of 15(R)-15-methyl-PGE 0.153 ml. of triethylamine, 0.142 ml. of isobutylchloroformate, and 0.453 g. of p-acetamidophenol, there is obtained a crude oily residue. This residue is dissolved in chloroform and left at about 25 C. until the excess starting phenol crystallizes out and is then filtered off. The filtrate is concentrated and subjected to silica gel chromatography, eluting with chloroformacetonitrile (3:2). The residue obtained by concentration of selected fractions, an oil, 0.25 g., having Rf 0.3 (TLC on silica gel in chloroformacetonitrile 3:2).

EXAMPLE 15 15(R)-l 5-Methyl-PGE p-Benzamidophenyl Ester (Formula lll-B) Following the procedure of Example 1 but using 0.175 g. of 15(R)-15-Methyl-PGE 0.100 ml. of triethylamine, 0.093 ml. of isobutylchloroformate, and 0.6 g. of p-benzamidophenol, .there is obtained a crude solid residue. This residue is subjected to silica gel chromatography, eluting with chloroform, chloroformacetonitrile (9:1), chloroform-acetonitrile (2:1), and chloroform-acetonitrile 1:3). The residue obtained by concentration of selected fractions is rechromatographed to remove traces of the starting phenol, thereby yielding a colorless oil, 0.173 g. This oil is crystallized from ethyl acetate on addition of hexane as the title compound, white free-flowing crystals, 0.153. g., m.p. 88.390.3 C., having Rf 0.5 (TLC on silica gel in acetonitrile -chloroform 1:1).

EXAMPLE 16 p-l-lydroxybenzaldehyde Semicarbazone Ester of l5(R)-l5-Methyl-PGE (Formula lll-J) ylamine, 0.142 ml. of isobutylchloroformate, and 0.546 I g. of p-hydroxybenzaldehyde semicarbazone, there is obtained a crude oily residue. This residue is dissolved in ethyl acetate and washed with aqueous 0.1 N. sodium phosphate buffer at pH 6.0. The organic phase is dried over sodium sulfate and concentrated to a white solid. The residue is subjected to preparative thin-layer chromatography using ethyl acetate-methanol (9: 1) and eluting with acetone-methanol (3:1 to yield a colorless oil. This oil is chromatographed on silica gel, eluting with acetonitrile. The residue obtained by concentration of selected fractions, a white solid, 0.160 g., is recrystallized from acetone on addition of water to give the title compound, white free-flowing crystals, 0.085 g., m.p. 92.3-93.3 C., having Rf 0.5 (TLC in acetonitrile-methanol 9:1

Following the procedures of Examples 1-16 but employing the racemic forms of the PG compounds, there are obtained the corresponding esters of racemic PG compounds. I

EXAMPLES 17-59 The substituted phenyl and naphthyl esters of PGE l5-methyl-PGE and l5(R)-l5-methyl-PGE of Tables l-lll below are obtained following the procedures of Example 1, wherein the prostaglandin compound is reacted in the presence of triethylamine and isobutylchloroformate with the appropriate hydroxy phenyl or naphthyl compound, listed in the Table. These phenols or naphthols are readily available or prepared by methods described herein or known in the art. The crude products, obtained by concentration under reduced pressure, are purified by means described herein or known in the art, including partitioning, solvent extraction, washing, silica gel chromatography, trituration, or crystallization.

Following the procedures of Examples l7-59 but employing the racemic forms of the PG compounds, there are obtained the corresponding esters of the racemic PG compounds.

TABLE I Esters of PGE:

Hydroxy Phenyl or Product PGE Ex. Naphthyl Compound ester of formula:

17 p-(p-benzamidobenzamido)- lll-D phenol 18 N-( p-tritylphenyl )-plll-M hydroxybenzamide l9 p-hydroxybenzoic acid. lll-N methyl ester 20 hydroquinone benzoate lll-O 2l hydroquinone, p-acetamidolll-P benzoic acid ester 22 2,4-diacetamidopl1enol I Ill-Q 23 l-acemmido-4-hydroxylll-R naphthalene 24 l-benzamido-4-hydroxylll-S naphthalene 25 l-hydroxy-4-ureido- Ill-T naphthalene TABLE 11 Esters of l5-Methyl-PGE Product 15- l-lydroxy Phenyl or Methyl-PGE Ex. Naphthyl Compound ester of formula:

26 p-(p-acetamidobenzamido)- lll-C phenol 27 p-(p-benzamidobenzamido)- lll-D phenol 28 p-hydroxyphenylurea "LE 29 p-phenylphenol lll-F 30 pitrity lphenol Ill-G 31 -aeetyltyrosinamide lll-H 32 N-benzoyltyrosinamidc "H 33 p-hydroxyacetophenone lll-K 34 'p-hydroxybenzamidelll-L 35 N-(ptritylphenyl)-p-' lll-M hydroxybenzamide 36 p-hydroxybenzoic acid. Ill-N methyl ester .37 hydroquinone benzoate 111-0 38 hydroquinone, p-acetamidolll-P benzoic acid ester 39 2,4-diacetamidophenol lll-Q 40 l-acctamido-4-hydroxylll-R naphthalene 41 1 -ben zamido-4-hydroxylll-S naphthalene: 42 ,l -hydro xy-4-ureidolll-T TABLE Ill Esters of l(l1)-l5-Mcthyl-PGE. l-lydroxy Phony] or Product l5(R)-l5-Mcthylll. An optically active compound of the formula:

or a racemic compound of that formula and the mirror image thereof, wherein Z is N f I I OH, or (13% x 0H, C H

2. An optically active compound of the formula:

I -NH-c- I and wherein Y IS H OH, CH

OH, CH

OI IC -CH -CH NH-C-CH 21 22 Q or a racemic compound of that formula and the mirror I} image thereof, wherein Z is -C-O-CH -U-NH-C-R1 I Kjflo-cwherein R1 IS s Ol O w-O- -NH-C-CH Q F- |i (2) R -NH-C-CH3 or H-CV-CHC,

O o (l H -NHC- or (3) -NH-C-R2 wherein R is -CH 0 ll -NH-C-NH m 1 z 4 and wherein Y is H OH, CH OH, C H OH, CH OH, or OH.

and wherein Y is H 0H, CH OH, C H OH, CH OH, or 6 H;

3. An optically active compound of the formula: 4. An optically active compound of the formula:

0 ll O ll HO H lC-(CH; 4-CH3 \bmHa VCHE 23 24 or a racemic compound of that formula and the mirror or a racemic compound of that formula and the mirror image thereof, wherein Z is image thereof, wherein Z is and wherein Y is H OH, CH OH, or Cit: H.

5. An optically active compound of the formula: 15 7CH5 J -NH a H /CH2\ (Ci|g):--C-O-Z I -NH--C-(C H )3 or =C H C'(CH2)4'CH3 O CH3; HO H i --3 l or a racemic compound of that formula and the mirror or (-2 -O .c 4 image thereof, wherein Z is ,7. The p-acetamidophenyl ester' of PGE a comi pound according to claim 1. 2- -C- H2 '8. The p-benzamidophenyl ester of PGE a compound according to claim 1. p" 9. The p-(p-acetamidobenzamido)phenyl ester of PGE a compound according to claim 1.

or -10. The ester of p-hydroxyphenylurea and PGE a compound according to claim 1. 0 11. The p-biphenyl ester of PGE a compound according to claim 1. --CH=N -NH- -NH 12. The p-tritylphenylcster of PGE a compound according to claim 1. i

4" t and wherein Y IS H OH, CH OH, C H OH, CH OH, o (T -H;-

6. An optically active compound of the formula: 13. The ester of N-acetyltyrosinamide and PGE a F, compound according to claim 1. 14. The ester of N-benzoyltyrosinamide and PGE a 0 [CH2 (CH2 compound according to claim 1.

15. The ester of p-hydroxybenzaldehyde semicarbazone and PGE a compound according to claim 1. H 16. The ester of p-hydroxyacetophenone and PGE C=Q C v a compound a'ccording to claim 1. HO H 2 1 1- 17. The ester of p-hydroxybenzamide and PGE-;, a

Y compound according to claim 1. 

1. AN OPTICALLY ACTIVE COMPOUND OF THE FORMULA:
 2. An optically active compound of the formula:
 3. An optically active compound of the formula:
 4. An opticaLly active compound of the formula:
 5. An optically active compound of the formula:
 6. An optically active compound of the formula:
 7. The p-acetamidophenyl ester of PGE2, a compound according to claim
 1. 8. The p-benzamidophenyl ester of PGE2, a compound according to claim
 1. 9. The p-(p-acetamidobenzamido)phenyl ester of PGE2, a compound according to claim
 1. 10. The ester of p-hydroxyphenylurea and PGE2, a compound according to claim
 1. 11. The p-biphenyl ester of PGE2, a compound according to claim
 12. The p-tritylphenyl ester of PGE2, a compound according to claim
 1. 13. The ester of N-acetyltyrosinamide and PGE2, a compound according to claim
 1. 14. The ester of N-benzoyltyrosinamide and PGE2, a compound according to claim
 1. 15. The ester of p-hydroxybenzaldehyde semicarbazone and PGE2, a compound according to claim
 1. 16. The ester of p-hydroxyacetophenone and PGE2, a compound according to claim
 1. 17. The ester of p-hydroxybenzamide and PGE2, a compound according to claim
 1. 18. The p-acetamidophenyl ester of 15-methyl-PGE2, a compound according to claim
 1. 19. The p-benzamidophenyl ester of 15-methyl-PGE2, a compound according to claim
 1. 20. The p-acetamidophenyl ester of 15(R)-15-methyl-PGE2, a compound according to claim
 1. 21. The p-benzamidophenyl ester of 15(R)-15-methyl-PGE2, a compound according to claim
 1. 22. The ester of p-hydroxybenzaldehyde semicarbazone and 15(R)-15-methyl-PGE2, a compound according to claim
 1. 23. Free-flowing crystals of a compound of the formula:
 24. Free-flowing crystals of a compound of the formula:
 25. Free-flowing crystals of a compound of the formula: 